Untitled

COGNITIVE NEUROSCIENCE AND NEUROPSYCHOLOGY
Time-dependent e¡ect of transcranial direct
current stimulation on the enhancement of
Suk Hoon Ohna, Chang-Il Parkd, Woo-Kyoung Yooe, Myoung-Hwan Kof, Kyung Pil Choia,
Gyeong-Moon Kimb, Yong Taek Leec and Yun-Hee Kima
Departments of aPhysical Medicine and Rehabilitation, Division for Neurorehabilitation, bNeurology, Stroke and Cerebrovascular Center, Samsung Medical
Center, cDepartment of Physical Medicine and Rehabilitation, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Suwon,
dDepartment and Research Institute of Rehabilitation Medicine,Yonsei University College of Medicine, Seodaemun-gu, Seoul, eDepartment of Physical
and Rehabilitation Medicine, Hallym University Sacred Heart Hospital, Pyoungchon-dong, Dongan-ku, Anyang and fDepartment of Physical Medicine and
Rehabilitation, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea
Correspondence toYun-Hee Kim, MD, PhD, Professor and Chairperson, Department of Physical Medicine and Rehabilitation, Division for
Neurorehabilitation, Stroke and Cerebrovascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong,
Gangnam-gu, Seoul,135 -710, Republic of Korea
Tel: + 82 2 3410 2824, 2818; fax: + 82 2 3410 0388; e-mail: [email protected], [email protected]
This work was carried out at Samsung Medical Center, Sungkyunkwan University School of Medicine.
Received 30 August 2007; accepted 26 September 2007
The time-dependent e¡ect of transcranial direct current stimula-
was signi¢cantly increased after 20 min of tDCS application, and
tion (tDCS) on working memory was investigated by applying
was further enhanced after 30 min of stimulation. This e¡ect was
anodal stimulation over the left prefrontal cortex.This single-blind,
maintained for 30 min after the completion of stimulation. These
sham-controlled crossover study recruited15 healthy participants.
results suggest that tDCS at 1mA enhances working memory
A three-back verbal working-memory task was performed
in a time-dependent manner for at least 30 min in healthy parti-
before, during, and 30 min after 1mA anodal or sham tDCS.
Anodal tDCS, compared with sham stimulation, signi¢cantly
improved working-memory performance. Accuracy of response
Keywords: anodal stimulation, transcranial direct current stimulation, working memory
memory in healthy participants is improved by 10 min of
Working memory is used for temporary storage and
continuous anodal stimulation at 1 mA, using 35-cm2-sized
manipulation of information, and plays a basic role in
electrodes over the prefrontal cortex, whereas Boggio et al.
long-term memory, language, and executive function [1].
[9] reported that continuous tDCS for 20 min at 2 mA
Working memory has long been associated with the
(but not at 1 mA) using the same-sized electrodes improved
prefrontal cortex, in which verbal working memory is
working memory in patients with Parkinson’s disease.
handled mainly by the left hemisphere and spatial working
Marshall et al. [8], however, applied intermittent tDCS for
memory by the right hemisphere [2]. Understandably,
15 min using smaller electrodes (8-mm diameter) over the
memory enhancement is a major field of interest for those
bilateral frontal lobes and reported a negative effect on
involved in cognitive neuroscience and rehabilitation. In
working memory. Therefore, it is conceivable that stimula-
addition to pharmacotherapeutic and psychotherapeutic
tion methods, intensity and duration, site of stimulation,
approaches, brain stimulation using magnetic or electrical
and size of electrode are all important variables in the effects
techniques has recently been investigated as a means of
of tDCS on working memory in healthy participants and in
enhancing memory. Transcranial direct current stimulation
those with brain disease. To our knowledge, no clear
(tDCS) changes the membrane potential and modulates
consensus has been established on a safe and cognitively
cerebral excitability [3,4]. In humans, anodal polarization
enhancing intensity and duration of tDCS.
increases the excitabilities of the motor, visual, and
In this study, we applied 1mA anodal tDCS to the left
prefrontal cortices, to improve motor learning, working
prefrontal cortex of healthy participants for up to 30 min,
and evaluated its cognitive-enhancing effects and the
Recently, the effect of tDCS on working memory was
residual effects after tDCS administration. We also investi-
investigated using different application methods with
gated participant concentration and fatigue versus applica-
variable results. Fregni et al. [5] reported that working
tion time, to evaluate the potential side effects of tDCS.
c Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
This study enrolled 15 healthy participants (age 26.573.5
years; 5 men, 10 women); they received both anodal and
sham tDCS over the left prefrontal cortex. All participantswere right-handed, and their mean time spent in full-time
education was 15.771.0 years. No participant had a history
of neuropsychiatric or cardiovascular disease. Writteninformed content was obtained from all participants beforethey entered the study, and the study protocol wasapproved by our local ethics committee.
Experimental protocolThis study was designed as a single-blind, crossover, sham-controlled experiment. All participants participated in bothanodal and sham tDCS. The order of stimulation was
counterbalanced and randomized across all participants. To
minimize carryover effects, the interval between tDCS
Initially, the participants were familiarized with the
cognitive tasks. Participants practiced the three-back verbalworking-memory task until response accuracy reached a
plateau. Working-memory assessments were performed
before (Baseline), during tDCS at 10 min (T1), at 20 min
(T2), at 30 min (T3), and 30 min after tDCS completion (T4)
(Fig. 1a). The five task sets and the stimuli presented in eachtask were randomized to avoid difficulty bias. Participant
(a) Experimental design. For familiarization purposes, partici-
concentration and fatigue were each recorded using a visual
pants practiced tasks 10 times, until working memories reached a plateau.
analog scale (i.e. 1 represented ‘no concentration or no
Each participant was tested every 10 min during anodal or sham stimula-
fatigue’ and 10 represented ‘highest levels of concentration or
tion, and at 30 min after stimulation. Anodal and sham stimulations wererandomized for each participant, and the order was counterbalanced
fatigue’) at the same times as the working-memory assessments.
across participants. The three-back verbal working-memory test con-sisted of Korean letters. (b) Participants were required to respond (press
a keyboard space bar) if the presented letter was the same as the letterpresented three stimuli before.
To evaluate changes in working memory during and aftertDCS, we used a three-back verbal working-memory taskthat was similar to the one previously described [5,9,10].
over 5 s. After the stimulator had been turned off, the
Participants were presented with a pseudorandom set of 28
electrodes were kept in place for 30 min. This method of
Korean letters. Stimuli were generated using SuperlabPro v.
sham stimulation has also been used in other tDCS studies
2.0 software (Cedrus Corporation, San Pedro, California,
USA). Each letter was displayed on a computer monitor for900 ms, followed by a blank screen for 100 ms betweenstimuli. Participants were required to memorize the letters
and to press the space bar on a keyboard with a left finger, if
The primary outcomes of this study were accuracy, error
the presented letter was the same as the letter presented
rate, and response time during/after anodal stimulation
three stimuli before (Fig. 1b). The total number of targets
versus sham stimulation. Analyses were performed using
was 30, and the total number of foil stimuli was 60.
SPSS 13.0 statistical software (Chicago, Illinois, USA).
Accuracy (number of correct responses/total targets), error
Evaluations performed at different times were analyzed
rate (number of incorrect responses/total foils), and
using repeated-measures analysis of variance. Posthoc
response time (interval between target presentation and
comparisons were made using Bonferroni-corrected t-tests,
pressing the space bar) were determined.
to determine whether stimulation time had an effect on theprimary outcome. The differences between anodal andsham tDCS at each assessment were analyzed by indepen-
Transcranial direct current stimulation application
dent t-tests. Data were reported as means and standard
Direct current was transferred using a pair of saline-soaked
deviations, and significance was accepted at Po0.05.
surface sponge electrodes (5 Â 5 cm), and was deliveredusing a constant current stimulator, Phoresor PM850(IOMED, Salt Lake City, Utah, USA). For anodal stimulation
of the left dorsolateral prefrontal cortex, the anode was
placed over F3 (according to the 10–20 international system
Accuracies measured at baseline did not differ between the
for electroencephalogram electrode placement), and the
anodal and sham tDCS groups. Accuracies recorded after 20
cathode was placed over the contralateral right supraorbital
(T2) and 30 (T3) minutes of stimulation, and at 30 min after
area. A constant current of 1 mA was applied for 30 min. For
completing stimulation (T4), however, differed significantly
sham stimulation, the same electrode placement was used,
from those after sham tDCS stimulation. Anodal tDCS
but the current was applied for 5 s, and was then tapered off
induced significantly larger increases in accuracy than sham
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Table 1 Changes in accuracy, error rate, and reaction time induced by tDCS
aSigni¢cant at Po0.05 vs. baseline.
bSigni¢cant at Po0.05 vs. previous test.
cSigni¢cant at Po0.05 vs. sham.T1, after 10 min of tDCS; T2, after 20 min of tDCS; T3, after 30 min of tDCS; T4, 30 min after completing tDCS.tDCS, transcranial direct current stimulation.
stimulation did at these time points (Po0.05), and accuracy
tDCS is known to induce a polarity-dependent excitability
at T3 was significantly higher than for sham (Po0.05).
shift of stimulated brain areas, which has a modulatory
Repeated-measures analysis of variance revealed that
effect on behavioral outcomes [4,13,14]. According to
extended treatment had a significant effect on accuracy
previous studies, the effect of tDCS on brain activity seems
(F¼5.37; Po0.01, Table 1, Fig. 2a).
to depend on stimulation polarity [4,15]. In particular,anodal tDCS is known to induce neuronal depolarization in
the neuronal membrane and to increase local excitability.
Error rates measured at T1, T2, T3, and T4 were not
Therefore, improvements in working memory observed
significantly different compared with baseline for real or
during this study are considered to be due to enhanced local
sham tDCS treatments (Table 1, Fig. 2b).
cortical excitability in the left dorsolateral prefrontal cortex.Furthermore, tDCS might have an additional effect on theneuronal network associated with working memory beyond
the sites of stimulation, as was demonstrated by a previous
Reaction times measured at T1, T2, T3, and T4 were not
significantly different compared with baseline for real or
Recently, many studies on the effects of tDCS on working
sham tDCS treatments (Table 1, Fig. 2c).
memory have been conducted in healthy participants and inpatients with brain disease [6,7,9,12]. These studies reported
diverse behavioral effects that might have been due to
Concentration and fatigue were recorded at T1, T2, T3,
different methodologies relating to electrode position,
and T4, and there was no significant difference between real
current intensity, duration of application, and diversity of
and sham tDCS (Table 1). All participants successfully
cognitive paradigms employed [5,9,13]. In patients with
completed the experimental procedure, and no participant
Parkinson’s disease, Boggio et al. [9] used 1 or 2 mA tDCS for
20 min with 35-cm2-sized electrodes, but found that workingmemory improved only after administration of 2 mA tDCS.Fregni et al. [5,16] demonstrated that 1mA anodal tDCS over
the left DLPFC in healthy participants increased working-
The results of this study indicated that anodal tDCS over the
memory performance after 10 min of stimulation, and found
left dorsolateral prefrontal cortex (DLPFC) enhanced verbal
that the behavioral results depended on the stimulation site
working memory in healthy participants in a time-depen-
and polarity. In contrast, Iyer et al. [6] reported that an
dent manner. The accuracy of verbal working-memory tasks
intensity of 2 mA (but not of 1 mA) for 20 min improved
increased after 10 min of tDCS application, and this effect
word generation in healthy participants. The mean age of the
was further enhanced by 30 min of stimulation. The
participants, however, differed in the above-mentioned
accuracies at 30 min of stimulation were significantly
studies; participants in Iyer’s study [6] were older on
different between anodal and sham tDCS. Furthermore, this
average than those in Fregni’s study. Importantly, age,
memory-enhancing effect was maintained at 30 min after
education level, and underlying disease might modulate
discontinuation of tDCS. Error rates, reaction times, con-
the effects of tDCS. Participants enrolled in this study were
centration, and fatigue did not change significantly during
healthy and young, and had spent more than 13 years in full-
or after intervention. To our knowledge, this is the first
time education, which might explain the positive effects of 1-
study to explore the time-dependent effects of tDCS on
mA tDCS on cognitive function in our study. Further studies
at different intensities would provide more information
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
stimulation. Repetitive transcranial magnetic stimulationstudies have also demonstrated cognitive improvements
and modulation of left DLPFC in healthy participants and in
patients with clinical depression [18,19] or Parkinson’s
disease [20]. These two noninvasive brain stimulationmethods are, however, dissimilar in terms of their strengthsand weaknesses [21,22]. The tDCS device is simple,
wearable, battery-powered, and allows participants to per-form their daily activities. Although the large electrode
limits the focality of the stimulation, it operates at lowcurrent densities. Moreover, the large electrode and low
current density allow protracted tDCS stimulation to beperformed safely over a large area. Therefore, tDCS canpresent benefits for stimulating the prefrontal cortex for an
extended period of time [5]. These unique advantages of
tDCS also make it more useful for promoting working
In this study, only the accuracy of the working-memory
task was improved, but not error rates or response times.
The accuracy of working memory can be mediated bycognitive processes such as encoding, maintenance, selec-
tion, and decision-making, which are considered to becrucial functions of the DLPFC. In contrast, error detection
might be mediated through coordinated function with other
brain areas like the cingulate or temporoparietal cortices
[23–25]. Therefore, it might not have been obviouslyimproved by tDCS administration to the DLPFC. Reaction
times were also unchanged in this study after tDCSapplication. Before the experiment, participants attended
familiarization sessions until their performances touched a
plateau. We were thus able to eliminate the ‘learning effect’
of the working-memory task. In addition, to exclude thepossible influence of the excited motor cortex in thestimulated hemisphere, we instructed participants to per-
form the tasks with their left hands while the left hemi-sphere was being stimulated. This might have preventedunwanted effects on reaction time owing to a spread ofcortical excitability. Moreover, concentration and fatigue
could have confounded the observed cognitive perfor-mances. These parameters were, however, no different after
anodal and sham stimulation, and were unchanged by
tDCS. These findings suggest that concentration and fatiguewere not influenced by tDCS, and that they did not affectthe results of our study.
Changes in accuracy (a), error rate (b), and reaction time (c),
induced by transcranial direct current stimulation (tDCS). (a) Accuracy
In conclusion, we found that anodal tDCS administered to
was improved by anodal tDCS. Repeated-measures analysis of variance
the left DLPFC at 1 mA has a time-dependent, positive
(ANOVA) showed a signi¢cant group Â time factor interaction (F¼5.37,
impact on working memory, without any noticeable side
Po0.01). *Signi¢cant at Po0.05 versus baseline. wSigni¢cant at Po0.05versus the previous test. zSigni¢cant at Po0.05 versus sham. (b) Error
effects, in healthy participants. Future studies should
rates were not changed by anodal or sham tDCS. (c) Reaction times were
address the durability of this effect after repeated tDCS
about time-dependent changes in working memory inhealthy and diseased participants. In this study, we limited
This study was supported by a KOSEF grant funded by the
tDCS application to 30 min for safety reasons [6,9,17]. tDCS
Korean government (MOST) (No. M10644000022-06N4400-
stimulation, nevertheless, increased working memory in a
time-dependent manner, and this effect was maintained at30 min after stimulation. The residual effects of single and
repetitive tDCS remain to be explored in further studies.
1. Baddeley A. Working memory. Science 1992; 255:556–559.
The excitability shifts induced by tDCS are comparable
2. Smith EE, Jonides J. Storage and executive processes in the frontal lobes.
with those achieved by repetitive transcranial magnetic
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
3. Lang N, Siebner HR, Ward NS, Lee L, Nitsche MA, Paulus W, et al. How
14. Nitsche MA, Niehaus L, Hoffmann KT, Hengst S, Liebetanz D, Paulus W,
does transcranial DC stimulation of the primary motor cortex alter
et al. MRI study of human brain exposed to weak direct current
regional neuronal activity in the human brain? Eur J Neurosci 2005;
stimulation of the frontal cortex. Clin Neurophysiol 2004; 115:2419–2423.
15. Nitsche MA, Seeber A, Frommann K, Klein CC, Rochford C, Nitsche MS,
4. Nitsche MA, Paulus W. Excitability changes induced in the human motor
et al. Modulating parameters of excitability during and after transcranial
cortex by weak transcranial direct current stimulation. J Physiol 2000; 527
direct current stimulation of the human motor cortex. J Physiol 2005;
5. Fregni F, Boggio PS, Nitsche M, Bermpohl F, Antal A, Feredoes E, et al.
16. Fregni F, Mattu U, Nitsche M, Lomarev M, Sato S, Feredoes EM. Safety
Anodal transcranial direct current stimulation of prefrontal cortex
and cognitive effect of frontal DC brain polarization in healthy
enhances working memory. Exp Brain Res 2005; 166:23–30.
individuals. Neurology 2005; 64:23–30.
6. Iyer MB, Mattu U, Grafman J, Lomarev M, Sato S, Wassermann EM.
17. Fregni F, Boggio PS, Lima MC, Ferreira MJ, Wagner T, Rigonatti SP, et al.
Safety and cognitive effect of frontal DC brain polarization in healthy
A sham-controlled, phase II trial of transcranial direct current stimulation
individuals. Neurology 2005; 64:872–875.
for the treatment of central pain in traumatic spinal cord injury. Pain 2006;
7. Marshall L, Molle M, Hallschmid M, Born J. Transcranial direct current
stimulation during sleep improves declarative memory. J Neurosci 2004;
18. Martis B, Alam D, Dowd SM, Hill SK, Sharma RP, Rosen C, et al.
Neurocognitive effects of repetitive transcranial magnetic stimulation in
8. Marshall L, Molle M, Siebner HR, Born J. Bifrontal transcranial direct
severe major depression. Clin Neurophysiol 2003; 114:1125–1132.
current stimulation slows reaction time in a working memory task. BMC
19. Moser DJ, Jorge RE, Manes F, Paradiso S, Benjamin ML, Robinson RG.
9. Boggio PS, Ferrucci R, Rigonatti SP, Covre P, Nitsche M, Pascual-Leone A,
magnetic stimulation. Neurology 2002; 58:1288–1290.
et al. Effects of transcranial direct current stimulation on working
20. Boggio PS, Fregni F, Bermpohl F, Mansur CG, Rosa M, Rumi DO, et al.
memory in patients with Parkinson’s disease. J Neurol Sci 2006; 249:31–38.
Effect of repetitive TMS and fluoxetine on cognitive function in patients
10. Mull BR, Seyal M. Transcranial magnetic stimulation of left prefrontal
with Parkinson’s disease and concurrent depression. Mov Disord 2005;
cortex impairs working memory. Clin Neurophysiol 2001; 112:1672–1675.
11. Siebner HR, Lang N, Rizzo V, Nitsche MA, Paulus W, Lemon RN, et al.
21. Wassermann EM, Grafman J. Recharging cognition with DC brain
Preconditioning of low-frequency repetitive transcranial magnetic
polarization. Trends Cogn Sci 2005; 9:503–505.
stimulation with transcranial direct current stimulation: evidence for
22. Webster BR, Celnik PA, Cohen LG. Noninvasive brain stimulation in
homeostatic plasticity in the human motor cortex. J Neurosci 2004;
stroke rehabilitation. NeuroRx 2006; 3:474–481.
23. Botvinick MM, Braver TS, Barch DM, Carter CS, Cohen JD. Conflict
12. Fregni F, Boggio PS, Santos MC, Lima M, Vieira AL, Rigonatti SP, et al.
monitoring and cognitive control. Psychol Rev 2001; 108:624–652.
Noninvasive cortical stimulation with transcranial direct current
24. Vossel S, Thiel CM, Fink GR. Cue validity modulates the neural correlates
stimulation in Parkinson’s disease. Mov Disord 2006; 21:1693–1702.
of covert endogenous orienting of attention in parietal and frontal cortex.
13. Kincses TZ, Antal A, Nitsche MA, Bartfai O, Paulus W. Facilitation of
probabilistic classification learning by transcranial direct current
25. Corbetta M, Kincade JM, Shulman GL. Neural systems for visual
stimulation of the prefrontal cortex in the human. Neuropsychologia
orienting and their relationships to spatial working memory. J Cogn
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.